Lung and heart transplants are more immunogenic, and less prone to tolerance induction than kidney transplants. We and others have shown that an autoimmune Th17 and B cell response to collagen type V (?1)(col V) and K?1tubulin often accompanies lung transplantation, while heart transplantation elicits a response to col V and vimentin. The risks associated with de novo autoimmunity to Col V, k?1tubulin, and vimentin are substantial - for example, post-transplant Th17 responses to col V were associated with a 10-fold higher risk of the most severe form of fibro-obliterative chronic rejection in lung transplants, known as bronchiolitis obliterans syndrome [BOS]. Why these particular self-antigens and not others are the main targets of autoimmunity in lung and heart transplants, is currently unknown. We recently discovered that memory-type Th17 immune responses to col V, k?1tubulin, and vimentin are revealed in normal healthy individuals upon removal of CD39+ regulatory T cells (Tregs) or blocking various Treg functions. This suggests that autoimmunity, rather than being a secondary consequence of alloimmunity, may precede alloimmunity in the case of heart & lung transplants. We propose to test the hypothesis that Col V, k?1tubulin, and vimentin-reactive T cells are natural type 17 TcR?? memory T cells, produced in the thymus during ontogeny along with natural Treg (nTreg) counterparts, the normal function of which lies in maintaining airway and vascular homeostasis. This hypothesis represents a paradigm shift in the current view of donor passenger T cells in heart & lung allografts, from that of an inconsequential component of graft immunogenicity, to that of a necessary component of successful graft outcome. We propose 3 specific aims: 1) to further characterize the human natural T memory response to col V, k?1tubulin, and vimentin; 2) to determine the intrathymic derivation and organ-specificity of nTh17 specific to these antigens; and 3) to determine whether, and if so, how, the transplant donor immune status vis a vis col V, k?1tubulin, and vimentin, and donor HLA-DR type influences transplant outcome, and whether manipulation of donor or donor MHCII-restricted host immune status can prevent acute/ chronic rejection, caused by induced (i)Th17 cells and B cells specific for col V . Incorporating natural Th17 and regulatory T cells in the overall strategy of immune management of the graft recipient may preserve well-regulated autoimmunity to col V, k?1tubulin, and vimentin and allow stable tolerance to develop.